DID - Oct. 9, 2007 Issue

Vol. 6 No. 198

HHS’ OIG to Review Generic Drug Applications, Clinical Investigators

HHS’ Office of Inspector General (OIG) will release several reports on FDA issues including generic drug applications, off-label drug marketing and electronic labeling, according to the office’s work plan for fiscal 2008.

OIG will continue to investigate the agency’s time frames for reviewing abbreviated new drug applications for generic drugs and find factors that slow the application process. The FDA had a backlog of approximately 1,000 generic drug applications in 2006, although the agency is required to make a decision on the applications within 180 days of submission. Approximately one-third of the backlogged applications had exceeded their 180-day limit, OIG said.

The office is already working on its generic drug application process review and expects to issue the report in fiscal 2008, the work plan said.

The FDA recently announced it approved or tentatively approved 682 generic drugs in fiscal 2007, more than ever before (DID, Oct. 5). The agency also introduced the Generic Initiative for Value and Efficiency program, which will help modernize and streamline the generic drug approval process.

OIG also will review the FDA’s oversight of allowable off-label drug promotion and its enforcement actions for illegal off-label marketing. The office plans to issue its report in fiscal 2008, according to the work plan.

The work plan announced several other new reviews, the results of which OIG intends to issue in reports in fiscal 2009. In one, OIG will investigate how the FDA regulates drug manufacturers’ compliance on electronically submitting drug labels for marketed prescription drugs. The office will investigate how accurate and complete the submitted labels are and identify factors that lead to misleading or missing information.

Two new OIG reviews will focus on issues with clinical investigators. One will investigate the FDA’s discipline actions against clinical investigators who have engaged in research misconduct. In 2002, OIG recommended the FDA develop an internal guidance on when a clinical investigator could be disqualified from receiving investigational products for a clinical trial. The new review will examine how the FDA is implementing that recommendation.

The other will review how clinical investigators disclose their financial conflicts of interest to the FDA, how applicants monitor their clinical investigators for conflicts of interest and how much the FDA oversees the process. Conflicts of interest can negatively influence data integrity and human subject protection, the work plan said.

Finally, OIG will determine whether the FDA is meeting the goals and time frames it established in its Pandemic Influenza Preparedness Strategic Plan.

OIG’s work plan for fiscal 2008 can be seen at oig.hhs.gov/publications/docs/workplan/2008/Work_Plan_FY_2008.pdf. — Emily Ethridge


HHS Awards Drugmakers $55.3 Million for Bioterrorism Countermeasures

Four companies were awarded contracts totaling $55.3 million for the development of anthrax antitoxins, therapeutics and antibiotics to treat plague and tularemia, HHS announced last week.

Tularemia is an illness caused by exposure to bacterium Francisella tularensis. If weaponized into aerosol form, the agent can cause severe respiratory illness and is life-threatening if left untreated, according to the Centers for Disease Control and Prevention.

“These contracts will help speed the development of new interventions against anthrax, plague and tularemia, three diseases considered to be important bioterror threats,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), said.

The following contracts were awarded to:

  • Emergent BioSolutions, $9.5 million to develop anthrax immune globulin;
  • Nanotherapeutics, $20 million to develop antibiotics that treat plague and tularemia; and
  • PharmAthene and Elusys Therapeutics, $13.9 million and $11.9 million, respectively, to develop anthrax antitoxins.

Emergent BioSolutions will receive funding for preclinical testing, as well as Phase I and II pharmacokinetics and safety studies under its contract, the company said. The product is designed as an intravenous treatment for patients already exposed to anthrax, where vaccination is not an option.

Previously, the firm inked a $449 million agreement with HHS for 18.75 million doses of its anthrax vaccine, BioThrax (anthrax vaccine adsorbed), for government stockpiling.

Nanotherapeutics reformulates generic medications that are poorly adopted due to drug delivery issues, the company said. The firm’s NanoGENT, an inhaled formulation of antibiotic gentamicin, is in preclinical testing for the treatment of exposure to biological warfare agents, tuberculosis and other respiratory infections.

PharmAthene and partner Medarex are developing anti-anthrax monoclonal antibody Valortim. The firm also is developing Protexia (butyrylcholinesterase recombinant), a treatment for exposure to nerve agents, under a $213 million contract from the Defense Department.

Elusys Therapeutics’ contract with HHS will fund continued development of anthrax therapeutic Anthim, an antibody in late-stage testing. The firm has received $32 million from HHS and the Defense Department for developing the drug, as well as development of its heteropolymer antibody technology. The technology uses a monoclonal antibody to bind target pathogens to red blood cells, facilitating their clearance and destruction via liver macrophages, the company said.

Separately, NIAID is soliciting proposals from manufacturers for vaccine adjuvants for use against Category A, B and C priority pathogens, infectious agents classified as posing the greatest threat against civilian populations. The initiative will fund early-stage development of candidate vaccines. — Christopher Hollis


Warnings in the Works for BMS, GE Ultrasound Drugs

Bristol Myers Squibb (BMS) and GE Healthcare are negotiating with the FDA about adding warnings for their ultrasound contrast drugs to the product labels.

The FDA is reportedly investigating incidents of deaths and serious cardiopulmonary reactions in patients taking BMS’ Definity (perflutren lipid microspheres) and GE Healthcare’s Optison (perflutren protein Type A microspheres), which are used to enhance ultrasound images for patients who need a diagnosis of their cardiovascular problems.

“We’re in negotiations with the FDA right now … about a label change for Definity,” BMS spokesperson Tony Plohoros told DID. “When used properly and in accordance with the label, we believe Definity is safe and provides medically important information.”

He said the company will confirm what the label changes are when they are complete.

“We are also talking with the FDA about label changes, and we are currently working with the FDA on how this should be implemented for Optison,” Brian McKaig, director of public relations for GE Healthcare, told DID. “To date, more than 1 million doses of Optison have been given, and very few adverse reactions have been reported.”

Among the safety warnings for Definity currently listed on BMS’ website are that it should not be administered to patients with known cardiac shunts nor by direct intra-arterial injection, and that extreme caution should be exercised in patients who may have cardiac shunts and in those with chronic pulmonary vascular disorders. The most frequently reported adverse events are headache, back or renal pain, flushing, nausea, chest pain and dizziness.

Similarly, the warnings listed for Optison on GE Healthcare’s website state that it “should be administered with caution in patients with cardiac shunts, congenital heart defects, confirmed or suspected severe liver disease, small cross-sectional pulmonary vascular surface areas or respiratory distress syndrome. Optison is contraindicated in patients with known or suspected hypersensitivity to blood, blood products or albumin.” The most frequently reported adverse events for the drug are headache, nausea or vomiting, warm sensation or flushing, and dizziness.

The FDA could not be reached for comment at press time. — Martin Gidron


Barr Settles With Massachusetts in Medicaid Fraud Case

Barr Laboratories and Duramed Pharmaceuticals, both subsidiaries of Barr Pharmaceuticals, have entered into a $2 million settlement agreement with the Massachusetts attorney general to resolve Medicaid price reporting litigation, Attorney General Martha Coakley’s office announced.

The commonwealth had sued 13 generic drugmakers in the U.S District Court for the District of Massachusetts in 2003 for allegedly inflating the prices they reported to national price reporting services.

The other companies involved with the suit are Mylan, Ivax, Warrick Pharmaceuticals, Watson Pharmaceuticals, Schein Pharmaceutical, Teva Pharmaceuticals, Par Pharmaceutical, Purepac Pharmaceutical and Roxane Laboratories, according to court records. The commonwealth has already settled with Ethex and Dey.

The claims against Barr and Duramed were related to methotrexate, naltrexone HCl, warfarin sodium, Apri (desogestrel/ethinyl estradiol) and digoxin, the attorney general said.

The Massachusetts Medicaid program uses prices reported by national price reporting services to determine the amounts it will pay for drugs dispensed to participants, the attorney general’s office said. The commonwealth alleged that by reporting inflated prices, the drugmakers caused the Medicaid program to pay inflated amounts for Medicaid recipients.

The complaint alleged that the defendants committed fraud and violated the Massachusetts Medicaid False Claims Act, among other counts.

“This is a national and industrywide problem that the commonwealth and other states and the federal government continue to address,” Coakley said Oct. 5. “Our office will continue to work with the Medicaid program, other law enforcement agencies and the federal government to implement a pharmaceutical reimbursement program that is fair to all parties and ensures continued coverage for our citizens.”

Barr Pharmaceuticals has agreed to pay the commonwealth $2 million while denying any wrongdoing and asserting its price reporting was consistent with legal standards, the office said. The company could not be reached for comment by press time. — Breda Lund


Merck Wins Vioxx Case in Florida

Merck won a product liability case over Vioxx when a jury of the Circuit Court of Hillsborough County, Fla., ruled the company was not liable for the plaintiff’s heart attack.

The plaintiff, Refik Kozic, claimed he used the company’s withdrawn painkiller Vioxx (rofecoxib) for approximately nine weeks before experiencing a heart attack in 2001.

“We believe that Mr. Kozic’s longstanding cardiovascular disease caused his heart attack,” Mike Brock, attorney with Rushton, Stakely, Johnston, and Merck’s outside counsel, said.

Evidence showed Kozic had significant atherosclerosis and coronary artery disease in the vessels that supply blood to the heart, according to Merck. Kozic also had high cholesterol and other cardiovascular risk factors, the company added.

The Vioxx case was the first in Florida to go to trial.

Merck has lost five Vioxx cases and won 11, although a federal judge set aside one of the verdicts in Merck’s favor. There have been two mistrials. Merck faces more than 27,000 lawsuits over Vioxx, according to the company. — Emily Ethridge

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Reporters: Martin Gidron, Emily Ethridge, April Astor, Breda Lund, Christopher Hollis

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